Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types

doi:10.1073/pnas.0504757102

Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types

McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, WI 53706

Edited by Bruce D. Hammock, University of California, Davis, CA, and approved October 11, 2005 (received for review June 7, 2005)

Abstract

The aryl hydrocarbon receptor (AHR) plays a role in three areas of biology that include the adaptive metabolism of xenobiotics, the toxic responses associated with exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), and vascular remodeling of the developing embryo. To test the hypothesis that receptor signaling in different cell types is responsible for these aspects of AHR biology, we generated a conditional Ahr allele where exon 2 is flanked by loxP sites. Through the use of Cre-lox technology, we then investigated the role of AHR signaling in hepatocytes or endothelial cells in mediating prototypical endpoints of adaptive, toxic, or developmental signaling. Using this model, we provide evidence that AHR signaling in endothelial/hematopoietic cells is necessary for developmental closure of the ductus venosus, whereas AHR signaling in hepatocytes is necessary to generate adaptive and toxic responses of the liver in response to dioxin exposure. Taken together, these data illustrate the importance of cell-specific receptor signaling for the generation of distinct AHR-dependent physiological outcomes.

Footnotes

↵ * To whom correspondence should be addressed. E-mail: bradfield{at}oncology.wisc.edu.
Author contributions: J.A.W. and C.A.B. designed research; J.A.W., E.G., K.P., and A.L.L. performed research; J.A.W. contributed new reagents/analytical tools; J.A.W. and C.A.B. analyzed data; and J.A.W. and C.A.B. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: AHR, aryl hydrocarbon receptor; ALT, alanine aminotransferase; ARNT, aryl hydrocarbon receptor nuclear translocator; Cre, Cre recombinase; DV, ductus venosus; Tek, Tie2 kinase promoter/enhancer.